This five year K08 Career Development Award proposal for Dr. Christopher Barbieri describes a career development program designed to culminate in a career as an independent investigator in Urologic Oncology. Dr. Barbieri is an urologist at Weill Cornell Medical College, committed to a career as a surgeon-scientist focused on the molecular characterization of prostate cancer. This Career Development Award will allow Dr. Barbieri to become an expert in the molecular characterization of prostate cancer, and translate this research into the clinical care of prostate cancer patients. Dr. Barbieri will be mentored by Dr. Mark Rubin, a leader in the field of prostate cancer genomics and molecular classification of the disease. Dr. Rubin is Vice Chair for Experimental Pathology and Director of the Institute for Precision Medicine at Weill Cornell Medical College, and has overseen the career development of numerous young investigators. Research training will be enhanced by an outstanding team of collaborators to allow development of skills in genomics, mouse modeling, and computational biology. Finally, an advisory committee composed of well-recognized individuals serving roles as clinicians, scientists, and institutional leaders will further guide career development. The research proposal focuses on genomic rearrangements, which play a critical role in the pathogenesis of prostate cancer. Recently described recurrent mutations in SPOP define a novel molecular subclass of prostate cancer characterized by striking increases in total genomic rearrangements compared to other subtypes. The central hypothesis of this proposal is that SPOP mutant prostate cancers have distinct management of DNA break formation and repair, leading to effects on genomic rearrangements, altered sensitivity to therapeutic agents, and potentially effects on patient prognosis. Specific Aims include: 1) To elucidate the role of SPOP mutation in the formation and repair of DNA breaks in prostate cells. 2) To determine the effect of SPOP mutation on the sensitivity of prostate cancer cells to therapeutic agents affecting DNA damage and repair. 3) To define the association of SPOP mutations with patient outcomes and deregulation of DNA damage pathways in a large, well annotated cohort of radical prostatectomy specimens. Together, these studies will define the role of SPOP mutations in genomic instability, nominate potential inhibitors of SPOP mutant prostate cancer, and define the effect of SPOP mutation on the outcomes of patients with prostate cancer.